B cells are a critical component of the immune response in mammals, as they are the cells responsible for antibody production (humoral immunity). B cells are quite diverse, and this diversity is critical to the immune system. Each B cell within the host expresses a different antibody—thus, one B cell will express antibody specific for one antigen, while another B cell will express antibody specific for a different antigen. In humans, each B cell can produce an enormous number of antibody molecules (i.e., about 107 to 108). The maturation of B cells (and thus antibody production) most typically ceases or substantially decreases when the foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell or plasma cell will continue unabated; such proliferation can result in a cancer referred to as “B cell lymphoma or multiple myeloma.”
B cell lymphomas include both Hodgkin's lymphoma and a broad class of non-Hodgkin's lymphoma. Cell lymphomas, such as the B-cell subtype of non-Hodgkin's lymphoma, are significant contributors to cancer mortality. The response of B-cell malignancies to various forms of treatment is mixed. For example, in cases in which adequate clinical staging of non-Hodgkin's lymphoma is possible, field radiation therapy can provide satisfactory treatment. Still, about one-half of the patients die from the disease. Devesa et al., J. Nat'l Cancer Inst. 79:701 (1987).
Non Hodgkin's lymphomas (NHL) are the most common hematologic malignancies in adults representing the sixth most commonly diagnosed cancer in North America and in Europe. Approximately 85% of NHL are of B-cell origin and comprise a heterogeneous group of malignancies, ranging from slow growing indolent and usually incurable diseases, to more aggressive but potentially curable lymphomas. CD22 is expressed in ˜60% to >90% of B-lymphoid malignancies of the majority of NHLs with B-cell origin.
Over the past two decades, major progress has been achieved in the management of NHL. The introduction of rituximab, a monoclonal antibody directed against the B-cell surface antigen CD20, has significantly improved treatment outcomes in most patients with NHL. Rituximab in combination with standard chemotherapy has improved response rate, progression free and overall survival in both indolent and aggressive lymphomas.
Despite therapeutic advances, treatment is still challenging for many patients with lymphomas. Traditional methods of treating B-cell malignancies, including chemotherapy and radiotherapy, have limited utility due to toxic side effects. Most lymphomas respond initially to any one of the current chemotherapeutic agents, but tumors typically recur and eventually become refractory. As the number of regimens patients receive increases, the more chemotherapy resistant the disease becomes. Average response to first line therapy is approximately 75%, 60% to second line, 50% to third line, and 35-40% to fourth line. Response rates with a single-agent in the multiple relapsed setting approaching 20% are considered positive and warrant further study.
Additionally, the period of remission following each treatment decreases. Patients with indolent lymphomas will invariably relapse and many will require additional treatments, while more than half of the patients with aggressive lymphomas will not be cured following standard treatments. In fact, many patients with diffuse large B-cell lymphoma (the most common subtype of aggressive lymphomas) are refractory to standard chemotherapy and/or chemoimmunotherapy regimens and relapses are frequent even in patients that achieve an initial response to treatment.
The prognosis for those affected by these diseases is poor, as the survival rates for lymphoma patients remain low. Salvage approaches based on high-dose chemotherapy with stem-cell transplantation are helpful only for selected patients and most patients succumb to their disease or to complications of intensive treatments. New methods for treating these diseases are needed.
Therefore, there is a need for the development of novel agents and treatment regimens with less toxicity and more specific targeting of tumor cells. Targeted therapies provide a promising alternative to standard cytotoxic chemotherapy. Unlike traditional chemotherapy, they affect specific targets present in the lymphoma cells and may spare normal tissues, thus minimize toxicity. The combination of agents that target specific components of pathways relevant to lymphomagenesis, with novel monoclonal antibodies represents a novel approach for the development of new treatment strategies in patients that are newly diagnosed, relapse or are refractory to Rituximab and standard chemotherapy.
Immunoconjugates comprising a member of the potent family of antibacterial and antitumor agents, known collectively as the calicheamicins or the LL-E33288 complex, (see U.S. Pat. No. 4,970,198 (1990)), were developed for use in the treatment of myelomas. The most potent of the calicheamicins is designated γ1, which is herein referenced simply as gamma. These compounds contain a methyltrisulfide that can be reacted with appropriate thiols to form disulfides, at the same time introducing a functional group such as a hydrazide or other functional group that is useful in attaching a calicheamicin derivative to a carrier. (See U.S. Pat. No. 5,053,394). The use of the monomeric calicheamicin derivative/carrier conjugates in developing therapies for a wide variety of cancers has been limited both by the availability of specific targeting agents (carriers) as well as the conjugation methodologies which result in the formation of protein aggregates when the amount of the calicheamicin derivative that is conjugated to the carrier (i.e., the drug loading) is increased. Inotuzumab ozogamicin (CMC544) is a CD22-specific immunoconjugate of calicheamicin in which a humanized IgG4 anti-CD22 mAb, G5/44, is covalently linked via an acid-labile AcBut linker to CalichDMH (Blood 2004; 103:1807-1814). CalichDMH (N-acetyl gamma calicheamicin dimethylhydrazide) is a derivative of gamma calicheamicin, a DNA-damaging enediyne antibiotic (Bioconj Chem 2002; 13:40-46). Gamma calicheamicin binds DNA in the minor groove and with the help of cellular thiols brings about double-strand DNA breaks (Science 1988; 240: 1198-1201) leading to cellular apoptosis and cell death. Antibody-targeted chemotherapy enables a cytotoxic agent to be delivered specifically to tumor cells by conjugating the cytotoxic agent with a monoclonal antibody that binds to a tumor-associated antigen. This strategy preferentially delivers the cytotoxic agent to tumor cells, minimizes exposure of normal tissues (lacking the targeted agent) to the cytotoxic agent, and results in a significantly improved therapeutic index.
Temsirolimus is a specific inhibitor of the mammalian target of rapamycin (mTOR), an enzyme that regulates cell growth and proliferation. Temsirolimus prevents progression from the G1 phase to the S phase of the cell cycle through inhibition of mTOR. The mTOR is a kinase that propagates signalling through growth factor pathways and regulates metabolic pathways that allow tumors to adapt to a harsh microenvironment. Inhibitors of mTOR, therefore, have the potential to inhibit tumor cell growth on at least two levels, a direct inhibitory effect on mutated growth factor signaling pathways and an indirect effect through inhibition of mTOR-regulated tumor survival factors.
Temsirolimus (CCI-779, rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid) is a structural analog of sirolimus (rapamycin) that has been formulated for IV or oral administration for the treatment of various malignancies. Temsirolimus is an antineoplastic agent. Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, which was found to have antifungal activity, particularly against Candida albicans, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot. 31, 539 (1978); U.S. Pat. No. 3,929,992; and U.S. Pat. No. 3,993,749]. Additionally, rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with picibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity.
Rapamycin is useful in preventing or treating adult T-cell leukemia/lymphoma [European Patent Application 525,960 A1] and malignant carcinomas [U.S. Pat. No. 5,206,018]. The preparation and use of hydroxyesters of rapamycin, including CCI-779, are disclosed in U.S. Pat. No. 5,362,718.
For patients with lymphomas relapsed or refractory to standard chemotherapy, improvements in outcomes may derive from the development of alternative treatment strategies with less toxicity and better targeting of the lymphoma cells. Basic and preclinical laboratory research have permitted to identify some of the pathways that are abnormally expressed in lymphomas and agents that target specific components of these pathways have entered clinical evaluation in recent years. While some of these agents have proven to be effective and associated with a better toxicity profile than standard chemotherapy, resistance has been often observed, limiting their clinical use.
The increase of the antitumor efficacy of a known antitumor compound by administering the same in combination with one or more different antitumor drugs in order to reduce the toxic effects of the individual agents when used alone, and because the combination has greater efficacy than when either agent is used alone, is a strongly felt need in the field of anticancer therapy. Moreover, improved anti-cancer therapies comprise a large unmet medical need and the identification of novel systemic therapies and combination regimens are required to improve treatment outcome by targeting all types of B cell malignancies. In particular, there is a need for a therapy which can overcome the shortcomings of current treatments regimens by using combination of immunoconjugates and small molecules to treat a variety of malignancies including hematopoietic malignancies like non-Hodgkin's lymphoma (NHL), without inducing an immune response. Such improved therapy has the advantage of targeting a diverse group of B cell malignancies by using two agents with different mechanism of actions. Further, non-Hodgkin lymphomas are a diverse group of blood cell cancers derived from lymphocytes, a type of white blood cell. As such, patients with different types of B-cell non Hodgkins lymphomas would benefit from the combination therapy of the present invention.
Moreover, the combination therapy of the present invention is potentially more effective and less toxic; and thus allows repeated administration of comparatively low dosage levels of two or more agents targeting different types of B-cell malignancies and for longer periods of treatment.
In addition to treating newly diagnosed patients, the novel combination therapy using combinations of targeted agents, such as ADCs, with a cytotoxic agent represents possible approach to overcome resistance that may be developed to treatment. Further, the enhanced antitumor activity of the combination therapy is particularly useful for patient population that relapse after treatment with inotuzumab ozogamicin or temsirolimus alone or where enhanced antitumor effect reduces toxicities associated with treatment using inotuzumab ozogamicin or temsirolimus alone. Accordingly, the present invention provides methods for enhancing the antitumor activity of inotuzumab ozogamicin and temsirolimus by a novel combination and sequential therapy regimen.